Niemann-Pick Disease type C (NPC) is a neurovisceral lysosomal lipid storage disorder that has a wide clinical spectrum. The disease may cause rapid fatality in neonates, or chronic neurodegenerative symptoms in children and adults. It can present hepatosplenomegaly (enlarged liver and spleen) in infants, children or adults. NPC is characterized by eye movement abnormalities, dysphagia (difficulty in swallowing) and dysarthria (slurred, irregular speech), ataxia (lack of muscle control), and progressive cognitive dysfunction (progressive intellectual decline) leading to dementia. NPC is also associated with impaired intracellular lipid trafficking, including the pathways for cholesterol, leading to lipid accumulation in the liver, spleen, and in the brain.
Based on molecular genetic testing, the cause of NPC has been identified as associated with autosomal recessively inherited loss-of-function mutations in in either the NPC1 or NPC2 genes. Niemann-Pick disease type D (NPD), previously and still sometimes used to describe the genetic isolate from Nova Scotia, is now associated with mutations in the NPC1 gene. The two genes regulate cholesterol homeostasis. NPC1 encodes a putative integral membrane protein containing sequence motifs consistent with a role in intracellular transport of cholesterol to post-lysosomal destinations. This protein binds cholesterol at its N-terminal domain and transports cholesterol to late endosomal/lysosomal compartments where they are hydrolyzed and released as free cholesterol. Defects in this gene, which account for 95% of NPC cases, cause over-accumulation of cholesterol and glycosphingolipids in late endosomal/lysosomal compartments. The NPC2 gene encodes a protein containing a lipid recognition domain that binds and transports cholesterol to the NPC1 protein. Mutation in NPC2 accounts for approximately 4% of NPC cases.
The diagnosis of NPC is confirmed by biochemical testing that demonstrates impaired cholesterol esterification and positive filipin staining in cultured fibroblasts. Biochemical testing to detect carrier status is unreliable. Most individuals with NPC have NPC1, caused by mutations in NPC1; fewer than 20 individuals have been diagnosed with NPC2, caused by mutations in NPC2. Molecular genetic testing of NPC1 and NPC2 detects disease-causing mutations in approximately 94% of individuals with NPC.
Treatment options for NPC are limited. Traditional treatment plans use medicines that aim to control or relieve specific symptoms of the disease. Currently, there is no FDA approved medicine that specifically targets NPC. Only one drug, miglustat (N-butyl-deoxynojirimycin), has been approved in Europe and other countries for the treatment of NPC. Therefore, a need still exists for novel and more effective methods of treating NPC.
GEX1A and pladienolide have previously been found to have respective antitumor activities (U.S. Pat. No. 5,719,179 (Mizukami et al.) and U.S. Pat. No. 8,008,049 (Machida et al.)). GEX1A was isolated in 1992 by researchers at the Monsanto Agricultural Company from microbial fermentation broths of Streptomyces chromofuscus, due to its herbicidal activity. GEX1A was later found to upregulate low density lipoprotein (LDL) receptor and lower plasma cholesterol. However, the plasma cholesterol cycle is separated by the blood-brain barrier from the central nervous system, where the accumulation of unesterified cholesterol is observed in the NPC phenotype. Accordingly, new therapies for the treatment of lysosomal lipid storage disorders such as NPC are needed. For example, new therapies that reduce cellular cholesterol storage are needed to improve current clinical therapies.